An NIMH Strategic Objective addresses the need for personalized medicine, that is, choosing the best treatment for a given individual. Findings of electrophysiologic studies have raised hopes for identifying predictors of clinical response to antidepressants. These studies have, however, been limited to EEG measures in standard frequency bands and conventional measures of auditory evoked potentials (N1, P2). This RO3 application proposes to do extensive time-frequency (TF) analyses of a unique data set from an RO1 project (MH36295; G. Bruder, PI), which will generate new findings concerning underlying time- and frequency-locked neural oscillations and may strengthen the predictive value of these electrophysiologic measures. The data were obtained in a study examining the value of electrophysiologic and neurocognitive measures for predicting clinical response to an SSRI antidepressant (escitalopram), an NDRI antidepressant (bupropion), or a combination of these treatments. The electrophysiologic measures, including resting EEG, event-related potentials (ERPs) during a novelty oddball task, and loudness dependency of auditory evoked potentials (LDAEPs) show promise of being able to differentiate patients who respond favorably to an SSRI and those who do not. These measures were administered in a pretreatment session and again during treatment to examine acute and chronic effects of these antidepressants. The proposed analyses will use a new approach to derive TF components from reference-free current source density measures. We will examine event-related oscillations and determine whether auditory ERP differences between treatment responders and nonresponders to novel stimuli result from event-related synchronization or phase-locking of midline theta activity, which is thought to involve orienting processes in anterior cingulate cortex. In addition to examining theta activity, we will test for predicted differences between responders and nonresponders in event-related gamma in the LDAEP paradigm. Lastly, we will determine whether there are changes in these TF measures following 12 weeks of treatment with an SSRI, NDRI or dual therapy with both antidepressants and examine the relation of these changes to improvement of depression and cognitive function. Results from a preclinical study, in which combined administration of SSRI and NDRI antidepressants had synergistic effects in increasing serotonin activity, led to the prediction that dual therapy will result in greater improvements in neurophysiologic and cognitive function than either antidepressant alone.